Recent studies suggest that chronic exposure to hypoxia causes a persistent attenuation of systemic vasoconstrictor reactivity that is not reversed upon re-exposure to normoxia. This alteration in vascular control may be responsible for the impaired ability of patients with lung disease associated with chronic hypoxia (CH) to respond adequately to cardiovascular stress. Recent work from our laboratory demonstrates that the vascular expression of heme oxygenase (HO) may be elevated following CR, with resultant enhanced production of the vasodilator carbon monoxide (CO). Several additional pilot studies strongly suggest that endogenous CO may be responsible for attenuated vasoconstrictor reactivity and may be an important component of vascular regulation under these clinically relevant conditions. Experiments planned for this proposal will validate the physiological significance of the HO/CO system as a regulator of vascular tone during CH. Thus, this proposal has the following specific aims: Specific Aim #1-Establish the time course and oxygen threshold for chronic hypoxia-induced attenuation of systemic vasoconstrictor reactivity. Specific Aim #2-Determine the functional differences that account for diminished constrictor reactivity in arterioles from chronically hypoxic rats compared to controls. Specific Aim #3-Demonstrate that in vivo attenuation of systemic vasoconstrictor reactivity following chronic hypoxia involves enhanced release of a heme oxygenase product. Specific Aim #4-Assess the vascular expression and activity of heme oxygenase in tissue from control and chronically hypoxic rats. Specific Aim #5-Establish the mechanisms by which endogenous CO diminishes constrictor responsiveness in arterioles from chronically hypoxic rats. The proposed experiments utilize a variety of in vivo and in vitro approaches to examine questions central to the regulation of the systemic circulation by a novel vasodilatory pathway under clinically relevant conditions.